ES2333943T3 - 2-ARIL-PROPIONIC ACIDS AND PHARMACEUTICAL COMPOSITIONS THAT CONTAIN THEM. - Google Patents

Abstract

Compounds of (R, S) -2-aryl-propionic acid of formula (Ia) and their individual (R) and (S) enantiomers: and pharmaceutically acceptable salts thereof, wherein Ar is a phenyl ring substituted in position 4 (para) with a group selected from C 1 -C 5-sulfonyloxy, substituted or unsubstituted benzenesulfonyloxy, C1-C5-sulfonylamino alkane, substituted or unsubstituted benzenesulfonylamino, C1-C5-sulfonylmethyl alkane, substituted or unsubstituted benzenesulfonylmethyl .

Description

Acids 2-aryl-propionics and compositions Pharmaceuticals that contain them.

Brief Description of the Invention

The present invention relates to acids (R, S) -2-aryl-propionics, to their individual enantiomers (R) and (S) and to compositions pharmaceuticals that contain them, which are used in prevention and tissue injury treatment due to exacerbated recruitment of polymorphonuclear leukocytes (PMN) neutrophils as sites of inflammation.

State of the art

Particular blood cells (macrophages, granulocytes, neutrophils, polymorphonuclear) respond to a chemical stimulus (when stimulated by substances called chemokines) migrating along the gradient of concentration of the stimulating agent by a procedure called chemotaxis. The main known stimulating agents or chemokines are represented by degradation products of complement C5a, some N-formylpeptides generated from the bacterial surface tisis or synthetic peptides such as formyl-methionyl-leucyl-phenylalanine (f-MLP) and mainly through a variety of cytokines that include interleukin 8 (IL-8). The Interleukin 8 is an endogenous chemotactic factor produced by the most nuclear cells such as fibroblasts, macrophages, endothelial and epithelial cells subjected to TNF-? stimulus (necrosis factor tumor), interleukins IL-1? e IL-1? And wall lipopolysaccharides bacterial (LPS), in addition to the same neutrophils exposed to the action of LPS or N-formylpeptides of origin bacterial (f-MLP). To the family of this factor chemotactic [also known as neutrophil activating factor (NAF), T lymphocyte chemotactic factor, chemotactic factor of monocyte derived neutrophils (MDNCF)] belongs a series of chemokines similar to IL-8 [GRO?, β, γ and NAP-2] that bind to IL-8 receptors (Chang et al. J. Immunol. 148, 451, 1992). Neutrophils are the first line of defense against bacterial infection due to the ability of these cells to migrate from peripheral blood through endothelial junctions and the tissue matrices towards the sites of action (i.e. length of concentration gradients of chemotactic factors) in those that act by attacking microorganisms, eliminating cells damaged and repairing tissues (M.A. Goucerot-Podicalo et al. Patol. Biol (Paris), 44, 36, 1996).

In some pathological conditions marked by exacerbated neutrophil recruitment, more tissue injury severe site is associated with cell infiltration neutrophils The activation function was recently demonstrated neutrophil in the determination of reperfusion associated injury after ischemia and pulmonary hyperoxia. The experimental models [N. Sekido et al. Nature, 365, 654, 1993 and T. Matsumoto et al. Lab Investig. 77, 119, 1997] and clinical studies [A Mazzone et al. Recent Prog. Med. 85, 397, 1994; G. Receipts et al. Atheroscl 91, 1, 1991] have shown the direct correlation between the lesion cell and the degree of PMN leukocyte infiltration, being the IL-8 the most specific and powerful activator of same. In patients affected by acute respiratory failure (ARDS), exacerbated recruitment of neutrophils in the pathways respiratory and pulmonary fluids can keep a correlation close to the concentration of cytokine IL-8 (E.J. Miller et al. Am. Rev. Respir. Dis. 146, 437, 1992) and with the severity of the pathology (Kurodowska et al. Immunol. 157, 2699, nineteen ninety six). It was shown that antibody treatment anti-IL-8 was effective in models of acute respiratory failure and lung injury caused by endotoxemia (K. Yokoi et al .; Lab. invest. 76, 375, 1997).

The specific function of IL-8 in the production of reperfusion injury after ischemia in patients affected by acute myocardial infarction (Y. Abe et al., Br. Heart J. 70, 132, 1993); the key function exerted by IL-8 in the mediation of the injury associated to reperfusion after ischemia is also corroborated by the results obtained using the antibody anti-IL-8 in an experimental model of focal cerebral ischemia in rabbits (T. Matsumoto et al. Lab. invest. 77, 119, 1997).

The biological activity of IL-8 it is mediated by the interaction of interleukin with CXCR1 and CXCR2 membrane receptors that belong to the family of seven transmembrane receptors expressed on the surface of human neutrophils and certain types of T cells (L. Xu and col., J. Leukocyte Biol. 57, 335, 1995).

Although it is known that the activation of CXCR1 plays a crucial role in chemotaxis mediated by IL-8, recently it has been assumed that the CXCR2 activation could play a pathophysiological function in  chronic inflammatory diseases such as psoriasis. In actually, the pathophysiological function of IL-8 in Psoriasis is also backed by the effects of IL-8 on keratinocyte functions.

In fact, it has been shown that the IL-8 is a potent proliferation stimulator of epidermal cells, in addition to angiogenesis, both aspects important aspects of psoriatic pathogenesis (A. Tuschil et al. J Invest  Dermatol, 99, 294, 1992; Koch AE et al., Science, 258, 1798, 1992).  Additionally, IL-8 induced the expression of HLA-DR remainder of the major complex of histocompatibility II (MHC-II) in keratinocytes cultivated (L. Kemény et al. Int Arch Allergy Immunol, 10, 351, nineteen ninety five). It is assumed that the effect of CXCL8 on the function of Keratinocytes are mediated by the activation of CXCR2. Agree With this hypothesis, it was reported that CXCR2 is overexpressed in skin with epidermal lesion of psoriatic patients (R. Kulke et al. J. Invest. Dermatol 110, 90, 1998). In addition, there are more and more evidence that the pathophysiological function of IL-8 in the progression of melanoma and metastasis could be mediated by CXCR2 activation.

The possible pathogenetic function of IL-8 in cutaneous melanoma is independent of its Chemotactic activity on human PMN. Actually, it’s supposed that IL-8 acts as a growth factor Autocrine and metastatic for melanoma cells.

It has been found that the concordant amount of CXL8 will be produced by melanoma cells and it is known that melanoma tumor cells express the CXCR2 receptor immunoreactive (L.R. Bryan et al. Am J Surg, 174, 507, 1997). Be know that IL-8 induces haptotactic migration, in addition to melanoma cell proliferation (J.M. Wang et al. Biochem Biophys Res Commun, 169, 165, 1990).

The possible function has been widely described pathogenic IL-8 in lung diseases (lung injury, acute dyspnoea syndrome, asthma, inflammation chronic lung and cystic fibrosis) and, specifically, in the pathogenesis of COPD (chronic obstructive pulmonary disease) by CXCR2 receiver route (D. WP Hay and H.M. Sarau. Current Opinion in Pharmacology 2001, 1: 242-247).

Phenylureide compounds have been described which can selectively antagonize the binding of IL-8 to the CXCR2 receptor (J.R. White et al. J. Biol. Chem. 273, 10095, 1998); the use of these compounds in the treatment of conditions pathological mediated by interleukin 8 is claimed in the WO 98/07418.

Studies on the contribution of individual (S) and (R) enantiomers of ketoprofen to activity anti-inflammatory racemate and its role in modulating Chemokine have been shown (P. Ghezzi et al. J. Exp. Pharm. Ther. 287, 969, 1998) that the two enantiomers and their salts with bases Organic chiral and non-chiral can inhibit in a way dose-dependent chemotaxis and increase concentration intracellular Ca2 + ions induced by IL-8 in human PMN leukocytes (patent application US6,069,172). Subsequently it has been demonstrated (C. Bizzarri et al. Biochem. Pharmacol 61, 1429, 2001) that ketoprofen shares the activity of inhibition of the biological activity of IL-8 with other molecules that belong to the class of anti-inflammatories Nonsteroidal (NSAIDs) such as furbiprofen, ibuprofen and indomethacin The cyclooxygenase enzyme inhibition activity Typical NSAID (COX) limits the therapeutic application of these compounds in the context of the treatment of pathological conditions dependent on neutrophils and inflammatory conditions such as psoriasis, idiopathic pulmonary fibrosis, respiratory failure acute, reperfusion lesions and glomerulonephritis. Inhibition of the synthesis of prostaglandins that derives from the action on Cyclo000xygenase enzymes implies increased production of cytokines that, like TNF-?, they play a role in amplifying the effects unwanted pro-inflammatory neutrophils.

The lower COX inhibitory potency of NSAID enantiomers (R) belonging to the subclass of phenylpropionic acids, compared to the potency of enantiomers (S), has suggested that the enantiomers (R) of ketoprofen, flurbiprofen and ibuprofen they may possibly be useful agents in the therapy of neutrophil-dependent pathologies. The fact that some enantiomers (R) become in vivo in the corresponding enantiomers (S) in various species of animals and humans, thus recovering COX inhibitory activity, is an important limit to the use of these compounds in therapy. of pathologies mediated by
IL-8

The premises explained briefly represent the great difficulties that have been found so far in the identification of selective IL-8 inhibitors belonging to the class of 2-phenylpropionic acids. It has been proposed that the chiral inversion of R enantiomers of 2-phenylpropionic acids is due to the stereospecific formation of the intermediate R-profenyl-CoA thioesters; therefore, it has been shown that derivatization of the carboxylic function allows to avoid metabolic inversion " in vivo " without affecting the efficacy of inhibition of
IL-8

Studies of the structure-activity relationship carried out in the class of 2-phenylpropionic acid derivatives led to the identification of novel classes of potent and selective inhibitors of biological activities of IL-8 suitable for " in vivo " administration. R-2-arylpropionic acid amides and N-acylsulfonamides have been described as effective inhibitors of chemotaxis and neutrophil degranulation induced by IL-8 (WO 01/58852; WO 00/24710).

         \ vskip1.000000 \ baselineskip
      

Detailed description of the invention

The inventors have now discovered that selected subclasses of 2-arylpropionic acids show the amazing ability to effectively inhibit chemotaxis and neutrophil degranulation induced by IL-8 without any obvious effect on activity of cyclooxygenases.

Both the R and S enantiomer of acids (R, S) -2-arylpropionics described later in this document they are in fact inactive in the inhibition of cyclooxygenases in a concentration range between 10-5 and 10-6 M.

         \ newpage
      

Therefore, the present invention provides (R, S) -2-arylpropionic acids of formula (la) and its individual (R) and (S) enantiomers:

one

and pharmaceutically salts acceptable of themselves;

in which Ar is a substituted phenyl ring in position 4 (for) with a selected group of C 1 -C 5 -sulfonyloxy, substituted or unsubstituted benzenesulfonyloxy, alkane C 1 -C 5 -sulfonylamino, substituted or unsubstituted benzenesulfonylamino, alkane C 1 -C 5 -sulfonylmethyl, substituted or unsubstituted benzenesulfonylmethyl.

The phenyl ring in the Ar group of formula (Ia) may be optionally substituted with other groups such as C 1 -C 5 alkyl or a group halogen

The term "substituted" in the definition above means substituted with a group selected from alkyl C 1 -C 5, halogen, hydroxy, alkoxy C 1 -C 5, amino, alkyl C 1 -C 5 -amino, nitro, or a cyano group

Particularly preferred compounds of The formula as defined earlier in this document are:

acid (R) 2- (4'-trifluoromethanesulfonyloxy) phenylpropionic

acid (S) 2- (4'-trifluoromethanesulfonyloxy) phenylpropionic

acid (R) 2- (4'-benzenesulfonyloxy) phenylpropionic

acid (S) 2- (4'-benzenesulfonyloxy) phenylpropionic

acid (R) 2- [4 '- (2' '- ethyl) benzenesulfonyloxy] phenylpropionic

acid (S) 2- [4 '- (2' '- ethyl) benzenesulfonyloxy] phenylpropionic

acid (R) 2- [4 '- (2' '- chloro) phenylsulfonyloxy] phenylpropionic

acid (S) 2- [4 '(2' '- chloro) phenylsulfonyloxy] phenylpropionic

acid (R) 2- [4 '- (2' '- propane) sulfonyloxy] phenylpropionic

acid (S) 2- [4 '- (2' '- propane) sulfonyloxy] phenylpropionic

acid (R) 2- (4'-benzylsulfonyloxy) phenylpropionic

acid (S) 2- (4'-benzylsulfonyloxy) phenylpropionic

acid (R) 2- (4'-aminosulfonyloxy) phenylpropionic

acid (S) 2- (4'-aminosulfonyloxy) phenylpropionic

acid (R) 2- (4'-trifluoromethanesulfonylamino) phenylpropionic

acid (S) 2- (4'-trifluoromethanesulfonylamino) phenylpropionic

acid (R) 2- (4'-methanesulfonylamino) phenylpropionic

acid (S) 2- (4'-methanesulfonylamino) phenylpropionic

acid (R) 2- [4 '- (2' '- propane) sulfonylamino] phenylpropionic

acid (S) 2- [4 '- (2' '- propane) sulfonylamino] phenylpropionic

acid (R) 2- (4'-benzenesulfonylamino) phenylpropionic

acid (S) 2- (4'-benzenesulfonylamino) phenylpropionic

acid (R) 2- [4 '- (2' '- ethyl) benzenesulfonylamino] phenylpropionic

acid (S) 2- [4 '- (2' '- ethyl) benzenesulfonylamino] phenylpropionic

acid (R) 2- [4 '- (2' '- chloro) benzenesulfonylamino] phenylpropionic

acid (S) 2- [4 '- (2' '- chloro) benzenesulfonylamino] phenylpropionic

acid (R) 2- (4'-benzylsulfonylamino) phenylpropionic

acid (S) 2- (4'-benzylsulfonylamino) phenylpropionic

acid (R) 2- (4'-aminosulfonylamino) phenylpropionic

acid (S) 2- (4'-aminosulfonylamino) phenylpropionic

acid (R) 2- (4'-trifluoromethanesulfonylmethyl) phenylpropionic

acid (S) 2- (4'-trifluoromethanesulfonylmethyl) phenylpropionic

acid (R) 2- (4'-benzenesulfonylmethyl) phenylpropionic

acid (S) 2- (4'-benzenesulfonylmethyl) phenylpropionic,

The compounds of the invention do not interfere with the production of PGE2 in murine macrophages stimulated with lipopolysaccharides (LPS, 1 µg / ml) during a concentration range: 10-5 to 10-6 M and, therefore, lack any inhibitory activity on cyclooxygenases (COX). Due to the absence of COX inhibitory activity in both the R and S enantiomers of the 2-phenylpropionic acids described, the compounds of the invention represent the first example of 2-phenylpropionic acids with the characteristics necessary for therapeutic use in pathologies related to chemotaxis and exacerbated activation of neutrophils induced by IL-8. The expected metabolic chiral inversion of the R enantiomers of the present invention gives the corresponding S enantiomers that
they share comparable characteristics in terms of potency of IL-8 and selectivity of COX with the R enantiomers.

The compounds of the invention of formula (Ia) they are generally isolated in the form of their base addition salts Pharmaceutically acceptable both organic and inorganic. Examples of such bases are: sodium hydroxide, potassium hydroxide, calcium hydroxide, (D, L) -Lysin, L-Lysine, tromethamine.

A procedure for acid preparation 2- (2-OH-phenyl) -propionics and its esters are described in Italian patent 1,283,649. A established and efficient procedure for the preparation of acid enantiomer R (R, S) -2- (5-benzoyl-2-acetoxy) -propionic and of the acids of formula (Ia) is the conversion of chlorides of said carboxylic acids in the corresponding prop-1-cetenos by reaction with a tertiary amine, for example, dimethyl ethyl amine, followed by reaction of the cetene with R (-) pantolactone to give the esters of R enantiomers of said acids with R-dihydro-3 hydroxy-4,4-dimethyl-2 (3H) furan-2-one.  Subsequent saponification of the ester with LiOH provides the corresponding free acids.

A general procedure for the preparation of R-2-arylpropionic acids from formula (Ia) implies, for example, the reaction of acid esters 4-hydroxy-phenylpropionics or esters of 4-aminophenylpropionic acids with chlorides of C 1 -C 5 -sulfonyl or chlorides of corresponding benzenesulfonyl in the presence of a base suitable organic or inorganic; or the reaction of acid esters 4-chloromethylphenylpropionics with C_ {1} -C_ {5} -thiolates or corresponding benzenethiolates in the presence of an organic base or suitable inorganic as described in detail in the section "General procedure for the synthesis of acids (S) and (R) -2 - [(4'-aryl / alkylsulfonylamino) phenyl] propionics of formula Ia "and following sections.

A typical preparation of compounds of formula (Ia) involves the reaction of hydroxyaryl ketones of formula (IIa) mono or polysubstituted with perfluorobutanesulfonyl fluoride to give perfluorobutanesulfonic esters of formula (IIb) in which n is an integer from 1 to 9:

2

The compounds of formula (IIb) are subjected to Willgerodt transposition in order to get after the esterification and methylation in alpha carbon derivatives arylpropionics of formula (IIc) in which n is an integer number of 1 to 9 and R 3 represents an alkyl C 1 -C 4 or alkenyl C_ {2} -C_ {4}.

3

The compounds of formula (IIc) are made react with the appropriate tributyl methanes of formula Bu 3 SnR 4 in which R 4 is an alkyl C 2 -C 6 linear or branched; alkenyl C 2 -C 6 linear or branched or alkynyl C 2 -C 6 linear or branched, unsubstituted or substituted with an aryl group, to obtain propionates of (R, S) -2-corresponding arito of formula (IId).

4

Alkenyl or alkynyl groups can hydrogenate under catalytic hydrogenation conditions in order to obtain the corresponding saturated alkyl groups. The Compounds of formula (IId) are subjected to the process of deracemization as described above for the conversion of the corresponding acid chlorides in cetenes which, by reaction with R (-) pantonolactone and subsequent hydrolysis, it they convert into pure R enantiomers; product reaction cetene intermediate with chiral auxiliary S (+) - pantonolactone gives the pure S enantiomer correspondent.

The compounds of the invention were evaluated in vitro for their ability to inhibit the chemotaxis of leukocytes and polymorphonuclear monocytes (hereinafter referred to as PMN) induced by the fractions of IL-8 and GRO-?. To this end, in order to isolate the PMNs from heparinized human blood taken from healthy adult volunteers, the mononuclear cells were removed by sedimentation on dextran (according to the procedure disclosed by WJ Ming et al. J. Immunol. 138, 1469, 1987) and erythrocytes through a hypotonic solution. The vitality of the cells was calculated by exclusion with trypan blue, while the ratio of the polymorphonuclear in circulation was estimated in the cytocentrifuge after staining with Diff Quick.

The recombinant human IL-8 (Pepro Tech) was used as a stimulating agent in the experiments of Chemotaxia giving practically identical results: the protein lyophilized was dissolved in a volume of HBSS containing albumin 0.2% bovine serum (BSA) to obtain a stock solution which had a concentration of 10-5 M that was to be diluted in HBSS at a concentration of 10-9 M for the tests of Chemotaxia

During the chemotaxis test (according to W. Falket et al. J. Immunol. Methods, 33, 239, 1980) filters were used without PVP with a porosity of 5 µm and micro cameras suitable for Replication

The compounds of the invention were evaluated at a concentration ranging from 10-6 to 10-10 M; for this purpose was added, at the same concentration, both to the pores lower as to the upper pores of the microcamera. The evaluation of the ability of the compounds of the invention to inhibit IL-8-induced chemotaxis of Human monocytes were carried out according to the procedure disclosed by Van Damme J. et al. (Eur. J. Immunol. 19, 2367, 1989).

The compounds of the invention show the additional property of effectively inhibiting PMN chemotaxis GRO? induced; This activity allows therapeutic use of these compounds in pathologies related to IL-8 in which the CXCR2 route participates specifically or in conjunction with CXCR1 signaling.

The following table reports the Biological activities of compounds that show high potency in PMN chemotactic inhibition induced by both IL-8 as per the selective agonist of CXCR2 GRO-?

Some examples of powerful are included selective GRO-? inhibitors.

         \ newpage
      

Dual inhibitors of activities biological induced by IL-8 and GRO-? Are considerably preferred in view of the therapeutic applications of interest, but the compounds described that act selectively on the receptor of IL-8 CXCR1 or the receiver of GRO-? / IL-8 CXCR2 can find useful therapeutic applications in the care of specific pathologies as described below.

5

All the compounds of the invention demonstrated a high degree of selectivity towards chemotaxis inhibition induced by IL-8 compared to chemotaxis induced by C5a (10-9 M) or f-MLP (10-8) M).

It was found that the compounds of formula (Ia), evaluated ex vivo in the blood as a whole according to the procedure disclosed by Patrignani et al. in J. Pharmacol. Exper. Ther. 271, 1705, 1994, were totally ineffective as inhibitors of cyclooxygenase (COX) enzymes.

In almost all cases, the compounds of formula (Ia) does not interfere with the production of induced PGE2 in murine macrophages by stimulation of lipopolysaccharides (LPS, 1 µg / ml) at a concentration ranging from 10-5 and 10-7 M. Inhibition of the production of PGE2 that may registering is almost at the limit of statistical significance, and more frequently it is less than 15-20% of the value basal. The reduced effectiveness in CO inhibition constitutes an advantage for the therapeutic application of compounds of the invention to the extent that the inhibition of the synthesis of prostaglandins constitute a stimulus for the cells of macrophages amplify the synthesis of TNF-? (induced by LPS or hydrogen peroxide) which is a mediator important of neutrophil activation and stimulation for interleukin-8 cytokine production.

In view of the experimental evidence treated previously and of the function performed by the interleukin-8 (IL-8) and congeners of it in the procedures that involve activation and neutrophil infiltration, the compounds of the invention are particularly useful in the treatment of a disease such as psoriasis (R. J. Nicholoff et al. Am. J. Patol. 138, 129, 1991). Other diseases that can be treated with the compounds of the Present invention are chronic inflammatory pathologies intestinal such as ulcerative colitis (Y. R. Mabida et al. Clin. Sci. 82, 273, 1992) and melanoma, obstructive pulmonary disease chronic (COPD), bullous pemphigoid, rheumatoid arthritis (M. Selz et al. J. Clin. Invest. 87, 463, 1981), idiopathic fibrosis (E. J. Miller, previously cited, and P. C. Carré et al. J. Clin. Invest. 88, 1882, 1991), glomerulonephritis (T. Wada et al. J. Exp. Med. 180, 1135, 1994) and in the prevention and treatment of injuries produced by ischemia and reperfusion.

CXCR1 activation inhibitors and CXCR2 find useful applications as detailed above, particularly in the treatment of inflammatory pathologies chronic (for example, psoriasis) in which the activation of both IL-8 receptors plays a  crucial pathophysiological function in the development of disease.

Actually, it is known that the activation of CXCR1 It is essential in PMN-mediated chemotaxis IL-8 (Hammond M et al., J Immunol, 155, 1428, nineteen ninety five). On the other hand, the activation of CXCR2 is assumed to be essential in epidermal cell proliferation mediated by IL-8 and the angiogenesis of psoriatic patients (Kulke R et al. J Invest Dermatol, 110, 90, 1998).

In addition, selective CXCR2 antagonists are considered particularly useful in therapeutic applications in the attention of important lung diseases such as disease chronic obstructive pulmonary COPD (D. WP Hay and H.M. Sarau. Current Opinion in Pharmacology 2001, 1: 242-247).

Therefore, another object of the present invention is to provide compounds for use in the treatment of psoriasis, ulcerative colitis, melanoma, chronic obstructive pulmonary disease (COPD), bullous pemphigoid, rheumatoid arthritis, fibrosis idiopathic, glomerulonephritis and in the prevention and treatment of  injuries caused by ischemia and reperfusion, in addition to the use of such compounds in the preparation of a medicament for the Disease treatment as described above. The pharmaceutical compositions comprising a compound of the invention and a suitable vehicle thereof are also within the Scope of the present invention. The compounds of the invention, together with an adjuvant, vehicle, diluent or excipient conventionally employed can actually get in the way of pharmaceutical compositions and unit dosages of themselves, and in such form they can be used as solids, such as filled tablets or capsules, or liquids such as solutions, suspensions, emulsions, elixirs, or capsules filled with them, all for oral use, or in the form of sterile injectable solutions for parenteral use (including subcutaneous). Such pharmaceutical compositions and forms unit pharmaceuticals thereof may comprise components in conventional proportions, with or without compounds or principles additional assets, and such unit dosage forms may contain any adequate effective amount of the active substance according to the expected daily dosing interval that is going to be used

When used as pharmaceutical products, The acids of this invention are normally administered in the form of A pharmaceutical composition Such compositions can be prepared in a manner well known in the pharmaceutical art and comprise the less an active compound. Generally, the compounds of this The invention is administered in a pharmaceutically effective amount. The amount of compound administered will actually be normally determined by a doctor in view of the relevant circumstances which include the condition to be treated, the route of administration  chosen, the actual compound administered, age, weight and response of the individual patient, the severity of the symptoms of patient, and the like.

The pharmaceutical compositions of the invention can be administered through a variety of routes that include oral, rectal, transdermal, subcutaneous, intravenous, intramuscular and intranasal. Depending on the planned route of administration, the compounds are preferably formulated as or compositions Injectable or oral. Compositions for administration via route oral can take the form of bulk liquid solutions or suspensions, or bulk powders. However, more commonly, Compositions are presented in unit dosage forms for facilitate accurate dosing. The term "forms unit pharmaceuticals "refers to physically units discrete suitable as unit dosages for subjects humans and other mammals, each unit containing an amount default active material calculated to produce the effect therapeutic effect, in association with a pharmaceutical excipient suitable. Typical unit dosage forms include pre-measured ampules or syringes previously filled with liquid compositions or pills, tablets, capsules or the like in the case of solid compositions. In such compositions, the Acid compound is normally a minor component (of about 0.1 to about 50% by weight or preferably from about 1 to about 40% in weight), the rest being various vehicles or excipients and processing aids useful to form the form of Desired dosage

         \ global \ parskip0.930000 \ baselineskip
      

Liquid forms suitable for oral administration may include an aqueous vehicle or not suitable aqueous with buffers, suspending agents and dispersants, dyes, aromas and the like. Liquid forms, which include the injectable compositions described later in this document are always saved in the absence of light so that it avoid any catalytic effect of light, such as formation of hydroperoxide or peroxide. Solid forms may include, for example, any of the following components, or compounds of a similar nature: a binder such as cellulose microcrystalline, gum tragacanth or gelatin; an excipient such as starch or lactose, a disintegrating agent such as alginic acid, Primogel, or corn starch; a lubricant such as stearate from magnesium; a slide such as colloidal silicon dioxide; a sweetening agent such as sucrose or saccharin; or an agent flavoring such as mint, methyl salicylate, or flavoring of Orange.

Injectable compositions are based normally in sterile injectable saline or saline buffered with phosphate or other injectable vehicles known in the technique. As mentioned above, the acid derivative of formula I in such compositions is normally a component minority that frequently ranges from 0.05 to 10% by weight  the rest being the injectable vehicle and the like. Dosage Average daily will depend on various factors, such as severity of the disease and the patient's conditions (age, sex and weight). The dose will generally vary from 1 mg or a few mg to 1500 mg of the compounds of formula (I) per day, optionally divided into multiple administrations. Therefore, they can also administered higher dosages thanks to the low toxicity of the compounds of the invention for long periods of weather.

\hbox{Easton,
Pensilvania.}

The components described above for compositions administered via route or injectables are merely representative. Other materials, in addition to processing techniques and the like, are explained in part 8 of "Remington's Pharmaceutical Sciences Handbook", 18th edition, 1990, Mack Publishing Company,

 \ hbox {Easton,
Pennsylvania.} 

The compounds of the invention can also be administered in forms of sustained release or systems of administration of sustained release drugs. They can also find a description of representative materials of Sustained release in the materials incorporated in the manual Remington as before.

The present invention should be illustrated by of the following examples.

In the description of the compounds of the Invention of formula (I) the agreement to indicate the absolute configurations of any chiral substituent that may be present in the substituent R 'of said compounds with prime signs (for example R ', S', S '', etc.). Abbreviations: THF: tetrahydrofuran; DMF: dimethylformamide; AcOEt: ethyl acetate, HOBZ: 1-hydroxybenzotriazole, DCC: dicyclohexylcarbodiimide.

General procedure for the synthesis of (S) and (R) -2 [(4'-aryl / alkylsulfonylamino) phenyl] propionic acid

 \ hbox {of formula Ia} 

The separation of the two enantiomers of commercial acid reagent 2- (4'-nitrophenyl) propionic is achieved by crystallization of salts of S - (-) or R - (+) - α-phenylethylammonium corresponding in ethanolic solution as described in Akgun H. et al. Arzneim.-Forsch./Drug Res. 46 (11), no. 9, 891-894 (1996).

Acid (S) -2- (4'-nitrophenyl) propionic

[α] D = -48.9 ° (c = 2; EtOH abs.);

1 H NMR (CDCl 3): δ 8.15 (d, 2H, J = 7 Hz); 7.47 (d, 2H, J = 7 Hz); 3.95 (sa, 1 H, COO H )); 3.78 (m, 1 H); 1.52 (d, 3H, J = 7 Hz).

Acid (R) -2- (4'-nitrophenyl) propionic

[α] D = -43.5 ° (c = 2; EtOH abs.);

1 H NMR (CDCl 3): δ 8.12 (d, 2H, J = 7 Hz); 7.49 (d, 2H, J = 7 Hz); 3.90 (sa, 1H, COO H )); 3.81 (m, 1 H); 1.50 (d, 3H, J = 7 Hz).

Methyl esters of acids 4'-nitrophenylpropionics

Acid dissolves (R) -2- (4'-nitrophenyl) propionic (4 mmol) in methanol (40 ml) and 96% H2SO4 is added dropwise (0.5 ml). The resulting solution is allowed to stir overnight. After evaporation of the solvent, the oily residue is Dissolve in diethyl ether and the organic phase is washed with a sat. solution NaHCO3 (2x30 ml), dried over Na2SO4 and evaporate under reduced pressure to give the product desired as a pale yellow oil.

Acid methyl ester (R) -2- (4'-nitrophenyl) propionic

[α] D = -48.3 ° (c = 2; EtOH abs.);

1 H NMR (CDCl 3): δ 8.12 (d, 2H, J = 7 Hz); 7.49 (d, 2H, J = 7 Hz); 3.75 (m, 1 H); 3.70 (s, 3 H); 1.51 (d, 3H, J = 7 Hz).

         \ global \ parskip1.000000 \ baselineskip
      

Acid methyl ester (S) -2- (4'-nitrophenyl) propionic

[α] D = + 49 ° (c = 2; EtOH abs.);

1 H NMR (CDCl 3): δ 8.11 (d, 2H, J = 7 Hz); 7.49 (d, 2H, J = 7 Hz); 3.78 (m, 1 H); 3.68 (s, 3 H); 1.51 (d, 3H, J = 7 Hz).

Methyl esters of acids (S) and (R) -2- (4'-aminophenyl) propionics

Both compounds are prepared by reduction of the nitro group as described in Ram S. et al. Tetrahedron Left 25, 3415 (1984) and in Barrett A.G.M. et al. Tetrahedron Left 29, 5733 (1988).

Acid methyl ester (S) -2- (4'-aminophenyl) propionic

[α] D = + 16.5 ° (c = 2; EtOH abs.);

1 H NMR (CDCl 3): δ 7.85 (d, 2H, J = 7 Hz); 7.45 (d, 2H, J = 7 Hz); 3.81 (m, 1 H); 3.67 (s, 3 H); 1.62 (d, 3H, J = 7 Hz).

Acid methyl ester (R) -2- (4'-aminophenyl) propionic

[α] D = -17.1 ° (c = 2; EtOH abs.);

1 H NMR (CDCl 3): δ 7.85 (d, 2H, J = 7 Hz); 7.45 (d, 2H, J = 7 Hz); 3.81 (m, 1 H); 3.66 (s, 3 H); 1.65 (d, 3H, J = 7 Hz).

Acids (R) -2 - [(4'-aryl / alkylsulfonylamino) phenylpropionics

To a solution of the acid methyl ester (R) -2- (4'-annnophenyl) propionic  (10 mmol) described above in acetone (20 ml) are added dry pyridine (15 mmol) or equivalent organic / inorganic base and arylsulfonyl chloride (or alkylsulfonyl) (10 mmol) and the resulting solution is allowed to stir overnight. After evaporation of the solvent, the oily residue is dissolved in CHCl 3 (30 ml) and the organic phase is washed with water (3 x 30 ml), dried over Na2SO4 and evaporated to give the product desired pure as a solid after temperature treatment overnight at isopropyl ether and filtration at vacuum of the precipitate.

To a solution of the methyl ester (6 mmol) in CH 3 OH (25 ml) 2N NaOH (12 mmol) is added and the mixture The resulting mixture is allowed to stir overnight at room temperature. The CH 3 OH is evaporated and the aqueous basic phase is acidified until pH = 2 by adding 12 N HCl dropwise; ethyl acetate is added and the Two phases separate. The organic extracts are washed in countercurrent with water (3 x 20 ml), dried over Na 2 SO 4 and evaporate under reduced pressure to give the product pure isolate as a solid after temperature treatment overnight environment in n-hexane and the vacuum filtration of the precipitate (yield 75% -100%).

         \ vskip1.000000 \ baselineskip
      

The following compounds have been synthesized according to the procedure described above:

Example 27 Acid (R) 2- (4 '- (benzenesulfonylamino) phenylpropionic

[α] D = -56.5 ° (c = 1; EtOH abs.);

1 H NMR (CDCl 3): 8.40 (sa, 1H, SO2 NH); 7.70 (d, 2H, J-8 Hz); 7.30 (m, 3 H); 7.05 (d, 2H, J = 8 Hz); 6.92 (d, 2H, J = 8 Hz); 3.45 (q, 1H, J = 7 Hz); 1.22 (d, 3H, J = 7 Hz).

         \ vskip1.000000 \ baselineskip
      

Example 28 Acid (R) 2- (4'-methanesulfonylamino) phenylpropionic

[α] D = -124.3 ° (c = 1; EtOH abs.);

1 H NMR (CDCl 3); δ 7.48 (sa, 1H, SO 2 NH); 7.35 (d, 2H, J = 8 Hz); 7.18 (d, 2H. J = 8 Hz); 6.55 (bs, 1H, SQ_ {2} N H); 3.80 (q, 1H, J = 7 Hz); 3.00 (s, 3 H); 1.55 (d, 3H, J = 7 Hz).

         \ vskip1.000000 \ baselineskip
      

Example 29 Acid (R) 2-1'4 '- (2' '- propane) sulfonylaminolfenylpropionic

[α] D = -110 ° (c = 1; EtOH abs.);

1 H NMR (CDCl 3): δ 7.21 (d, 2H, J = 8 Hz); 7.05 (d, 2H, J = 8 Hz); 6.20 (sa, 1 H, SO 2 N H ); 3.65 (q, 1H, J = 7 Hz); 3.23 (m, 1 H); 1.50 (d, 3H, J = 7 Hz); 1.30 (d, 6H, J = 7 Hz).

         \ vskip1.000000 \ baselineskip
      

Example 30 Acid (R) 2- (4'-trifluoromethanesulfonylamino) phenylpropionic

[α] D = -84.5 ° (c = 1; EtOH abs.);

1 H NMR (CDCl 3): δ 7.25-7.05 (m, 4H); 7.00 (sa, 1 H, SO 2 N H ); 3.60 (q, 1H, J = 7 Hz); 1.41 (d, 3H, J = 7 Hz).

         \ vskip1.000000 \ baselineskip
      

Example 31 Acid (R) 2- (4'-benzylsulfonylamino) phenylpropionic

[α] D = -47 ° (c = 1; EtOH abs.);

1 H NMR (CDCl 3): δ 7.53 (m, 5H); 7.31 (d, 2H, J = 7 Hz); 7.15 (bs, 1H, SO {2} N H); 7.02 (d, 2H, J = 7 Hz); 4.65 (s, 2H); 3.80 (m, 1 H); 1.55 (d, 3H, J = 7 Hz).

         \ vskip1.000000 \ baselineskip
      

Example 32 Acid (R) 2- [4 '- (2' '- chloro) benzenesulfonylaminolfenylpropionic

[α] D = -81.5 ° (c = 1; EtOH abs.);

1 H NMR (CDCl 3): δ 7.95 (d, 1H, J = 8 Hz); 7.40 (m, 2 H); 7.22 (m, 1 H); 7.10 (m, 2 H); 6.95 (m, 2H + SO2N H ); 3.55 (q, 1H, J = 7 Hz); 1.35 (d, 3H, J = 7 Hz).

         \ vskip1.000000 \ baselineskip
      

Example 33 Acid (R) 2- [4 '- (2' '- ethyl) benzenesulfonylaminolfenylpropionic Chloride Preparation 2-ethylbenzenesulfonyl

Starting from 2-ethylbenzenethiol commercially, the related sulfonic acid is prepared as described in Trahanovsky W.S. "Oxidation in Organic Chemistry", vol. 5-D, 201-203 Academic Press, Inc, (London), 1982. The treatment of sulfonic acid with excess thionyl chloride gives the chloride Pure 2-ethylbenzenesulfonyl to be used in the condensation with acid methyl ester R (-) - 2- (4'-aminophenyl) propionic.

[α] D = -95 ° (c = 1; EtOH abs.);

1 H NMR (CDCl 3): δ 9.30 (sa, 1H, SO 2 N H ); 7.70 (d, 2H, J = 8 Hz); 7.25 (m, 4H); 7.08 (d, 2H, J = 8 Hz); 3.41 (q, 1H, J = 7 Hz); 2.70 (q, 2H, J = 8 Hz); 1.42 (d, 3H, J = 8 Hz); 1.22 (d, 3H, J = 7 Hz).

         \ vskip1.000000 \ baselineskip
      

Example 34 Acid (R) 2- (4'-aminosulfonylamino) phenylpropionic

[α] D = -110 ° (c = 1; EtOH abs.);

1 H NMR (CDCl 3): δ 7.95 (d, 2H, J = 8 Hz); 7.54 (sa, 2H, NSO 2 N H 2); 6.98 (m, 2H + SO 2 N H ); 3.57 (q, 1H, J = 7 Hz); 1.30 (d, 3H, J = 7 Hz).

         \ vskip1.000000 \ baselineskip
      

         \ global \ parskip0.900000 \ baselineskip
      

General procedure for the synthesis of (S) and (R) -2 - [(4'-aryl / alkylsulfonyloxy) phenylpropionic acids of

 \ hbox {formula Ia} 

The separation of the two enantiomers of commercial acid reagent 2- (4'-hydroxyphenyl) propionic is achieved by crystallization of the salts of S (-) or R (+) - α-phenylethylammonium corresponding in ethanolic solution as described in Akgun H. et al. Arzneim.-Forsch./Drug Res. 46 (11), no. 9, 891-894 (1996).

Acid (S) -2- (4'-hydroxyphenyl) propionic

[α] D = + 12 ° (c = 2; EtOH abs.);

1 H NMR (CDCl 3): δ 7.31 (d, 2H, J = 7 Hz); 7.05 (d, 2H, J = 7 Hz); 6.25 (sa, 1 H, OH); 3.80 (q, 1H, J = 7 Hz); 1.52 (d, 3H, J = 7 Hz).

Acid (R) -2- (4'-hydroxyphenyl) propionic

[α] D = -12.5 ° (c = 2; EtOH abs.);

1 H NMR (CDCl 3): δ 7.30 (d, 2H, J = 7 Hz); 7.07 (d, 2H, J = 7 Hz); 6.35 (sa, 1 H, OH); 3.75 (q, 1H, J = 7 Hz); 1.50 (d, 3H, J = 7 Hz).

Acid methyl ester (R) and (S) -2- (4'-hydroxyphenyl) propionic

Acid dissolves (2R) -2- (4'-hydroxyphenyl) propionic (4 mmol) in CH 3 OH (40 ml) and added dropwise H_ {2} SO_ {4} conc. (0.5 ml). The resulting solution is left shake overnight. After evaporation of the solvent, the oily residue is dissolved in depyl ether and the organic phase Wash with a sat solution. NaHCO3 (2 x 30 ml), dried over Na2SO4 and evaporate under reduced pressure giving the desired product as a pale yellow oil.

Acid methyl ester (R) 2- (4'-hydroxyphenyl) propionic

[α] D = -78 ° (c = 2; EtOH abs.);

1 H NMR (CDCl 3): δ 7.32 (d, 2H, J = 7 Hz); 7.10 (d, 2H, J = 7 Hz); 6.40 (sa, 1 H, OH); 3.70 (m, 4 H); 1.53 (d, 3H, J = 7 Hz).

Acids (R) 2 - [(4'-aryl / alkylsulfonyloxy) phenylpropionics

A mixture of the acid methyl ester (2R) -2- (4'-hydroxyphenyl) propionic (2 mmol) described above and arylsulfonyl chloride (or alkylsulfonyl) (2 mmol) in dry pyridine (1 ml) or in the presence of equivalent organic / inorganic base is heated at T = 60 ° C for 24 hours. After cooling to room temperature, the mixture of reaction is poured into 1 N HCl (5 ml) and the aqueous solution is extract with CH 2 Cl 2 (3 x 10 ml). Organic extracts collected are washed countercurrent with 1 N NaOH (2 x 10 ml), dried over Na2SO4 and evaporated under reduced pressure giving a pure pure residue sufficient to be used for the following stage (yield 80-92%).

A mixture of the crude methyl ester (1.85 mmol), glacial acetic acid (2.5 ml) and 37% HCl (0.5 ml) is subjected to reflux for 18 hours. All solvents are removed by evaporation, the oily residue is dissolved in CH2Cl2 (5 ml) and the organic phase is washed with 1 N NaOH (2 x 5 ml) and with water (2 x 10 ml), dried over Na2SO4 and evaporated under pressure reduced by giving (2R) aryl acids (or pure alkyl) sulphonyloxyphenylpropionics with a yield quantitative.

The following compounds have been synthesized according to the procedure described above:

Example 35 Acid (R) 2- (4'-benzenesulfonyloxy) phenylpropionic

[α] D = -66.2 ° (c = 1; EtOH abs.);

1 H NMR (CDCl 3): δ 7.92 (d, 2H, J = 7 Hz); 7.70 (t, 1H, J = 7 Hz); 7.57 (t, 2H, J = 7 Hz); 7.25 (d, 2H, J = 7 Hz); 6.95 (d, 2H, J = 7 Hz); 3.75 (q, 1H, J = 7 Hz); 1.50 (d, 3H, J = 7 Hz).

         \ vskip1.000000 \ baselineskip
      

Example 36 Acid (R) 2- (4'-benzylsufonyloxy) phenylpropionic

[α] D = -84.6 ° (c = 1; EtOH abs.);

1 H NMR (CDCl 3): δ 7.50 (m, 5H); 7.28 (d, 2H, J = 7 Hz); 7.05 (d, 2H, J = 7 Hz); 4.53 (s, 2 H); 3.77 (m, 1 H); 1.52 (d, 3H, J = 7 Hz).

         \ global \ parskip0.880000 \ baselineskip
      

Example 37 Acid (R) 2- (4'-Trifluoromethanesulfonyloxy) phenylpropionic

[α] D = -28.5 ° (c = 1; CH 3 OH);

1 H NMR (CDCl 3): δ 7.45 (d, 2H, J = 7 Hz); 7.22 (d, 2H, J = 7 Hz); 3.82 (q, 1H, J = 7 Hz); 1.51 (d, 3H, J = 7 Hz).

         \ vskip1.000000 \ baselineskip
      

Example 38 Acid (R) 2- [4 '- (2' '- propane) sulfonyloxy] phenylpropionic

[α] D = -42.8 ° (c = 1; CH 3 OH);

1 H NMR (CDCl 3): δ 7.41 (d, 2H, J = 7 Hz); 7.25 (d, 2H, J = 7 Hz); 3.82 (q, 1H, J = 7 Hz); 3.45 (q, 1H, J = 7 Hz); 1.52 (m, 9H).

         \ vskip1.000000 \ baselineskip
      

Example 39 Acid (R) 2- [4 '- (2' '- chloro) benzenesulfonyloxyphenylpropionic

[α] D = -43 ° (c = 1; EtOH abs.);

1 H NMR (CDCl 3): δ 7.90 (d, 1H, J = 8 Hz); 7.44 (m, 2H); 7.20 (m, 1 H); 7.12 (m, 2H); 6.95 (d, 2H, J = 8 Hz); 3.52 (q, 1H, J = 7 Hz); 1.38 (d, 3H, J = 7 Hz).

         \ vskip1.000000 \ baselineskip
      

Example 40 Acid (R) 2- [4 '- (2' '- ethyl) benzenesulfonyloxyphenylpropionic Chloride Preparation 2-ethylbenzenesulfonyl

Starting from 2-ethylbenzenethiol commercially, the related sulfonic acid is prepared as described in Trahanovsky W.S. "Oxidation in Organic Chemistry", vol. 5-D, 201-203 Academic Press, Inc, (London), 1982. Treatment of sulfonic acid with excess of thionyl chloride gives the chloride of Pure 2-ethylbenzenesulfonyl to be used in the condensation with acid methyl ester (R) -2- (4'-hydroxyphenyl) propionic.

[α] D = -104 ° (c = 1; EtOH abs.);

1 H NMR (CDCl 3): δ 7.71 (d, 2H, J = 8 Hz); 7.25 (m, 4H); 7.12 (d, 2H, J = 8 Hz); 3.44 (q, 1H, J = 7 Hz); 2.71 (q, 2H, J = 8 Hz); 1.45 (d, 3H, J = 8 Hz); 1.20 (d, 3H, J = 7 Hz).

         \ vskip1.000000 \ baselineskip
      

Example 41 Acid (R) 2- (4'-aminosulfonyloxy) phenylpropionic acid

[α] D = -91.5 ° (c = 1; EtOH abs.);

1 H NMR (CDCl 3): δ 7.95 (d, 2H, J = 8 Hz); 7.84 (sa, 2H, NSO 2 N H 2); 6.95 (d, 2H, J = 8 Hz); 3.61 (q, 1H, J = 7 Hz); 1.35 (d, 3H, J = 7 Hz).

         \ vskip1.000000 \ baselineskip
      

Procedure for the synthesis of acids (S) and (R) -2 - [(4'-arylalkyl sulfonylmethyl) phenyl] propionics of formula Ia Example 42 Acid (R) 2-4'-benzenesulfonylmethyl) phenylpropionic

The title product is prepared by a multi-stage synthesis starting from acid (R) -2-phenylpropionic commercial. Following the procedure described in EP 0 889 020 (Ex. 4), the acid (R) -2 - [(4'-chloromethyl) phenyl] propionic  It is prepared with good performance. The acid is transformed into the methyl ester by a usual procedure and the ester is added to a cooled mixture of benzenethiol / tert-butoxide potassium / 18-crown-6 (1: 1,1: 0,95) and, after the overnight reaction and the final treatment usual (washed with water, dried over Na2SO4 and evaporation of the solvent), the derivative of pure benzenethiomethyl and is used in the next oxidation stage. Oxidation to the related sulfone by 2 equivalents of 3-Chloroperoxybenzoic acid and the final treatment with NaOH / dioxane at room temperature it allows to isolate the product desired with good final yield (65% starting from acid (R) -2 - [(4'-chloromethyl) phenyl] propionic).

         \ global \ parskip1.000000 \ baselineskip
      

[α] D = -125 ° (c = 1; EtOH abs.);

1 H NMR (CDCl 3): δ 7.90 (m, 2H); 7.44-7.20 (m, 3H); 7.12 (d, 2H, J = 8 Hz); 6.95 (d, 2H, J = 8 Hz); 3.72 (s, 2H); 3.55 (q, 1H, J = 7 Hz); 1.43 (d, 3H, J = 7 Hz).

         \ vskip1.000000 \ baselineskip
      

Example 43 Acid (R) 2- (4'-trifluorometasulfonylmethyl) phenylpropionic

Following the procedure described in US 5,245,039 (09/14/1993) and starting from (R) -2 - [(4'-chloromethyl) phenyl] propionic acid methyl ester, (R) -2- Related [(4'-thiomethyl) phenyl] propionic is obtained in high yield (85%). The trifluoromethanethiomethyl derivative is obtained by treating the thiolate (generated " in situ " with 1 equivalent of potassium tert-butoxide) with the commercial trifluoromethyl iodide. The following oxidation to the sulfone derivative (by treatment with 2 equivalents of 3-chloroperoxybenzoic acid) and the final hydrolysis of the ester by NaOH / dioxane at room temperature allows the desired product to be isolated with quite a good final yield (47% starting from acid (R ) -2 - [(4'-chloromethyl) phenyl] propionic).

[α] D = -86 ° (c = 1; EtOH abs.);

1 H NMR (CDCl 3): δ 7.14 (d, 2H, J = 8 Hz); 7.02 (d, 2H, J = 8 Hz); 3.85 (s, 2H); 3.51 (q, 1H, J = 7 Hz); 1.48 (d, 3H, J = 7 Hz).

List of example structures

7

Claims (8)

1. Acid Compounds (R, S) -2-aryl-propionic of formula (Ia) and its individual (R) and (S) enantiomers: 8 and pharmaceutically salts acceptable of themselves, in which Ar is a substituted phenyl ring in position 4 (for) with a selected group of C 1 -C 5 -sulfonyloxy, substituted or unsubstituted benzenesulfonyloxy, alkane C 1 -C 5 -sulfonylamino, substituted or unsubstituted benzenesulfonylamino, alkane C 1 -C 5 -sulfonylmethyl, substituted or unsubstituted benzenesulfonylmethyl. 2. Compounds according to claim 1 selected from: acid (R) 2- (4'-trifluoromethanesulfonyloxy) phenylpropionic acid (S) 2- (4'-trifluoromethanesulfonyloxy) phenylpropionic acid (R) 2- (4'-benzenesulfonyloxy) phenylpropionic acid (S) 2- (4'-benzenesulfonyloxy) phenylpropionic acid (R) 2- [4 '- (2' '- ethyl) benzenesulfonyloxy] phenylpropionic acid (S) 2- [4 '- (2' '- ethyl) benzenesulfonyloxy] phenylpropionic acid (R) 2- [4 '- (2' '- chloro) phenylsulfonyloxy] phenylpropionic acid (S) 2- [4 '(2' '- chloro) phenylsulfonyloxy] phenylpropionic acid (R) 2- [4 '- (2' '- propane) sulfonyloxy] phenylpropionic acid (S) 2- [4 '- (2' '- propane) sulfonyloxy] phenylpropionic acid (R) 2- (4'-benzylsulfonyloxy) phenylpropionic acid (S) 2- (4'-benzylsulfonyloxy) phenylpropionic acid (R) 2- (4'-aminosulfonyloxy) phenylpropionic acid (S) 2- (4'-aminosulfonyloxy) phenylpropionic acid (R) 2- (4'-trifluoromethanesulfonylamino) phenylpropionic acid (S) 2- (4'-trifluoromethanesulfonylamino) phenylpropionic acid (R) 2- (4'-methanesulfonylamino) phenylpropionic acid (S) 2- (4'-methanesulfonylamino) phenylpropionic acid (R) 2- [4 '- (2' '- propane) sulfonylamino] phenylpropionic acid (S) 2- [4 '- (2' '- propane) sulfonylamino] phenylpropionic acid (R) 2- (4'-benzenesulfonylamino) phenylpropionic acid (S) 2- (4'-benzenesulfonylamino) phenylpropionic acid (R) 2- [4 '- (2' '- ethyl) benzenesulfonylamino] phenylpropionic acid (S) 2- [4 '- (2' '- ethyl) benzenesulfonylamino] phenylpropionic acid (R) 2- [4 '- (2' '- chloro) benzenesulfonylamino] phenylpropionic acid (S) 2- [4 '- (2' '- chloro) benzenesulfonylamino] phenylpropionic acid (R) 2- (4'-benzylsulfonylamino) phenylpropionic acid (S) 2- (4'-benzylsulfonylamino) phenylpropionic acid (R) 2- (4'-aminosulfonylamino) phenylpropionic acid (S) 2- (4'-aminosulfonylamino) phenylpropionic acid (R) 2- (4'-trifluoromethanesulfonylmethyl) phenylpropionic acid (S) 2- (4'-trifluoromethanesulfonylmethyl) phenylpropionic acid (R) 2- (4'-benzenesulfonylmethyl) phenylpropionic acid (S) 2- (4'-benzenesulfonylmethyl) phenylpropionic 3. Compounds according to claims 1 and 2 For use as medications. 4. Use of the compounds of the claims 1 and 2 in the preparation of a medicament for the treatment of psoriasis, ulcerative colitis, melanoma, lung disease chronic obstructive (COPD), bullous pemphigoid, arthritis rheumatoid, idiopathic fibrosis, glomerulonephritis and in the prevention and treatment of injuries caused by ischemia and reperfusion 5. Pharmaceutical compositions comprising a compound according to claim 1 and 2 in admixture with a vehicle suitable. 6. Compound preparation procedure according to claim 1, wherein Ar is C 1 -C 5 -sulfonyloxyphenyl or benzenesulfonyloxyphenyl, which comprises reacting esters of 4-hydroxy-phenylpropionic acids with chlorides of C 1 -C 5 -sulfonyl or chlorides of corresponding benzenesulfonyl, in the presence of a base suitable organic or inorganic. 7. Compound preparation procedure according to claim 1, wherein Ar is C 1 -C 5 -sulfonylaminophenyl or benzenesulfonylaminophenyl, which comprises reacting esters of 4-aminophenylpropionic acids with chlorides of C 1 -C 5 -sulfonyl or chlorides of corresponding benzenesulfonyl, in the presence of a base suitable organic or inorganic. 8. Compound preparation procedure according to claim 1, wherein Ar is C 1 -C 5 -sulfonylmethylphenyl or benzenesulfonylmethylphenyl, which comprises reacting esters of 4-chloromethylphenylpropionic acids with C_ {1} -C_ {5} -thiolates or corresponding benzenethiolates, in the presence of an organic base or adequate inorganic.